5R-[(benzyloxy)amino] piperidine-2S-carboxylate and 5R-[(benzyloxy)amino] piperidine-2S-carboxylate oxalate are key intermediates for preparing avibactam.
As a non-β-lactam inhibitor, one of diazabicyclooctanone compounds, avibactam may inhibit type-A (including ESBL and KPC) and type C β-lactamases. When administered in combination with various types of cephalosporins and carbapenem antibiotics, avibactam has a broad spectrum activity against bacteria, particularly has a significant activity against the Escherichia coli and Klebsiella pneumoniae containing ultra-broad spectrum β-lactamases, Escherichia coli containing excessive AmpC enzyme, and Escherichia coli containing both AmpC and ultra-broad spectrum β-lactamases. The sodium salt form of avibactam is shown in Formula I, whose CAS number is 1192491-61-4, with a chemical name of [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] sodium sulphate.

5R-[(benzyloxy)amino]piperidine-2S-carboxylate is a key intermediate for preparing avibactam (I). The patent WO2012172368 discloses a synthesis process for 5R-[(benzyloxy)amino]piperidine-2S-carboxylate and avibactam; the U.S. patents US2010197928 and US2013012712 disclose a synthesis of 5R-[(benzyloxy)amino]piperidine-2S-carboxylate (see scheme 1). Briefly, the N-protected L-pyroglutamate as the starting material is ring-opened with trimethylsulfoxonium iodide to add the carbon chain, the carbonyl of it is converted to imine by benzyloxyimino, and then the intermediate is deprotected under an acidic condition to remove protecting group, cyclized under an alkaline condition, and finally reduced by a reducing agent and subjected to chiral resolution to obtain a product IIb. The starting material and trimethylsulfoxonium iodide used in this process are expensive, and the total yield is not high.

US20140275001 discloses another synthesis process (scheme 2), wherein the N-protected L-pyroglutamate is still utilized as the starting material and is ring-opened with trimethylsulfoxonium iodide to add the carbon chain. The difference lies in that in the patent US20140275001, the cyclization is firstly carried out by an iridium catalyst to obtain an alcohol with S-conformation through selective reduction; and then inversion of configuration is realized by using N-benzyloxy-2-nitrobenzenesulfonamide and hydroxyl is converted into amino; 2-nitrobenzenesulfonyl chloride group is first removed under the action of lithium hydroxide and mercaptoacetic acid, and then the N-protecting group is removed by trifluoroacetic acid to obtain the product. The process has a complicated operation and uses the expensive iridium catalyst, and the total yield is only 15%.

Scheme 1 and Scheme 2 above adopt relatively expensive starting materials and a method of adding the carbon chain by trimethylsulfoxonium iodide; further, Scheme 2 uses the expensive iridium catalyst. The two reaction processes need protection and deprotection, such that the operations are very complicated; besides, they use a large amount of solvents and discharge a large amount of waste water, waste gas, and waste residuals, which are not environment-friendly and have a low atomic economy. Meanwhile, the two methods have a low yield and do not facilitate industrial production.